tbuckley/cabot-search huggingface dataset:
How location and cellular signaling combine to activate the NLRP3 inflammasome
Authors: Anil Akbal, Alesja Dernst, Marta Lovotti, Matthew S. J. Mangan, Róisín M. McManus, Eicke Latz
Journal: Cellular and Molecular Immunology (2022)

Abstract NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by infection and sterile inflammation. Upon detection of an activating stimulus, NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome, which promotes the helical oligomeric assembly of the adaptor molecule ASC. ASC oligomers provide a platform for caspase-1 activation, leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D, which can induce a lytic form of cell death. Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation. This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles. We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.
EP08.01-002 Real-World Survival Outcomes of Patients with High PD-L1 Advanced NSCLC Who Received Chemo-Immunotherapy vs Immunotherapy
Authors: J. Cheng, C. McKay, V.J. Bray, P.Y. Yip, A. Tognela, P.S. Kok
Journal: Journal of Thoracic Oncology (2022)
EP08.02-071 Brain Metastases in EGFR-mutant NSCLC: Outcome of Osimertinib +/- Radiation Therapy in a Real-World Canadian Cohort
Authors: I. Litt, A. Gibson, M. Dean, A. Elegbede, G. Bebb, W. Cheung, A. Pabani
Journal: Journal of Thoracic Oncology (2022)
IgM-secreting diffuse large B-cell lymphoma: results of a multicentre clinicopathological and molecular study
Authors: M. Christina Cox, Luigi Marcheselli, Giorgia Scafetta, Carlo Visco, Stefan Hohaus, Ombretta Annibali, Gerardo Musuraca, Alberto Fabbri, Maria Cantonetti, Sabrina Pelliccia, Robel Papotti, Luigi Petrucci, Monica Tani, Roberta Battistini, Annalisa Arcari, Stefano Luminari, Gianluca Lopez, Eleonora Alma, Livio Pupo, Giuseppe Carli, Francesco Marchesi, Francesca Re, Stefania Scarpino, Emanuele S. G. D’amore, Luigi M. Larocca, Antonella Bianchi, Giuseppina Pepe, Fiammetta Natalino, Paola Anticoli-Borza, Natalia Cenfra, Alessandro Andriani, Elisabetta Abruzzese, Cristiano Tesei, Lorenzo Leoncini, Silvia Asioli, Luigi Ruco, Arianna Di Napoli
Journal: Leukemia (2022)
Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair
Authors: Christopher O. Audu, William J. Melvin, Amrita D. Joshi, Sonya J. Wolf, Jadie Y. Moon, Frank M. Davis, Emily C. Barrett, Kevin D. Mangum, Hongping Deng, Xianying Xing, Rachel Wasikowski, Lam C. Tsoi, Sriganesh B. Sharma, Tyler M. Bauer, James Shadiow, Matthew A. Corriere, Andrea T. Obi, Steven L. Kunkel, Benjamin Levi, Bethany B. Moore, Johann E. Gudjonsson, Andrew M. Smith, Katherine A. Gallagher
Journal: Cellular and Molecular Immunology (2022)

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3
Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy
Authors: Paolo Strati, Andrew P. Jallouk, Ryan Sun, Jaihee Choi, Kaberi Das, Hua-Jay Cherng, Sairah Ahmed, Hun J. Lee, Swaminathan P. Iyer, Ranjit Nair, Loretta J. Nastoupil, Raphael E. Steiner, Chad D. Huff, Yao Yu, Haleigh Mistry, Brittany Pulsifer, Mansoor Noorani, Neeraj Saini, Elizabeth J. Shpall, Partow Kebriaei, Christopher R. Flowers, Jason R. Westin, Michelle A. T. Hildebrandt, Sattva S. Neelapu
Journal: Leukemia (2022)
Protecting procedural care—cybersecurity considerations for robotic surgery
Authors: William J. Gordon, Naruhiko Ikoma, Heather Lyu, Gretchen Purcell Jackson, Adam Landman
Journal: npj Digital Medicine (2022)

Cybersecurity is an increasingly important concern for reliable healthcare delivery and is particularly salient for robotic surgery. Surgical robots are complex systems with numerous points of vulnerability, and there have been real-world demonstrations of successful cyberattacks on surgical robots. There are several ways to improve the risk profile of robotic surgery, including recognizing system complexity, investing in regular software updates, following cybersecurity best-practices, and increasing transparency for all stakeholders. As robotic surgery continues to technologically advance, ensuring overall system safety from a cybersecurity perspective is paramount.
Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma
Authors: Anais Hagege, Esma Saada-Bouzid, Damien Ambrosetti, Olivia Rastoin, Julien Boyer, Xingkang He, Julie Rousset, Christopher Montemagno, Jérome Doyen, Florence Pedeutour, Julien Parola, Isabelle Bourget, Frederic Luciano, Alexandre Bozec, Yihai Cao, Gilles Pagès, Maeva Dufies
Journal: Cell Reports Medicine (2022)

Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.
Integrated multimodal artificial intelligence framework for healthcare applications
Authors: Luis R. Soenksen, Yu Ma, Cynthia Zeng, Leonard Boussioux, Kimberly Villalobos Carballo, Liangyuan Na, Holly M. Wiberg, Michael L. Li, Ignacio Fuentes, Dimitris Bertsimas
Journal: npj Digital Medicine (2022)

Artificial intelligence (AI) systems hold great promise to improve healthcare over the next decades. Specifically, AI systems leveraging multiple data sources and input modalities are poised to become a viable method to deliver more accurate results and deployable pipelines across a wide range of applications. In this work, we propose and evaluate a unified Holistic AI in Medicine (HAIM) framework to facilitate the generation and testing of AI systems that leverage multimodal inputs. Our approach uses generalizable data pre-processing and machine learning modeling stages that can be readily adapted for research and deployment in healthcare environments. We evaluate our HAIM framework by training and characterizing 14,324 independent models based on HAIM-MIMIC-MM, a multimodal clinical database (N=34,537 samples) containing 7,279 unique hospitalizations and 6,485 patients, spanning all possible input combinations of 4 data modalities (i.e., tabular, time-series, text, and images), 11 unique data sources and 12 predictive tasks. We show that this framework can consistently and robustly produce models that outperform similar single-source approaches across various healthcare demonstrations (by 6-33%), including 10 distinct chest pathology diagnoses, along with length-of-stay and 48-hour mortality predictions. We also quantify the contribution of each modality and data source using Shapley values, which demonstrates the heterogeneity in data modality importance and the necessity of multimodal inputs across different healthcare-relevant tasks. The generalizable properties and flexibility of our Holistic AI in Medicine (HAIM) framework could offer a promising pathway for future multimodal predictive systems in clinical and operational healthcare settings.
How do I wean a patient with acute hypercapnic respiratory failure from noninvasive ventilation?
Authors: A. Özsancak Uǧurlu, B. Ergan
Journal: Pulmonology (2022)

Noninvasive ventilation (NIV) has been increasingly used for the management of different etiologies of acute hypercapnic respiratory failure (AHRF). Although NIV implementation has been framed well by the guidelines, limited number of studies evaluated the NIV weaning strategies, including a gradual decrease in the level of ventilator support and/or duration of NIV as well as abrupt discontinuation, once respiratory acidosis and distress have resolved. None of the methods have yet been established to be superior to the other in terms of the success rate of weaning and duration of NIV; as well as mortality, length of stay (LOS) in hospital, respiratory ICU (RICU), and ICU. Patient-derived factors, such as etiology of AHRF, disease severity, history of prior NIV use, and clinical status can help to predict NIV weaning outcome and eventually choose the best method for each individual. In this paper, we have described the strategies for weaning a patient with AHRF from NIV and provided a quick guide for implementation of these data into daily practice based on our experience in and the current scientific evidence.
Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors
Authors: Elham Kashani, Désirée Schnidrig, Ali Hashemi Gheinani, Martina Selina Ninck, Philipp Zens, Theoni Maragkou, Ulrich Baumgartner, Philippe Schucht, Gunnar Rätsch, Mark A Rubin, Andrej Benjak, Rémy Bruggmann, Federico Comoglio, André Kahles, Irene Keller, Charlotte K Y Ng, Salvatore Piscuoglio, Laurie Prélot, Gunnar Rätsch, Mark A Rubin, Désirée Schnidrig, Senija Selimovic-Hamza, Tinu M Thomas, Sabina Berezowska, Charlotte K Y Ng, Erik Vassella
Journal: Neuro-Oncology (2022)

Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention.In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas.Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor.Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implications since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.
Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models
Authors: Borislav Dejanovic, Tiffany Wu, Ming-Chi Tsai, David Graykowski, Vineela D. Gandham, Christopher M. Rose, Corey E. Bakalarski, Hai Ngu, Yuanyuan Wang, Shristi Pandey, Mitchell G. Rezzonico, Brad A. Friedman, Rose Edmonds, Ann De Mazière, Raphael Rakosi-Schmidt, Tarjinder Singh, Judith Klumperman, Oded Foreman, Michael C. Chang, Luke Xie, Morgan Sheng, Jesse E. Hanson
Journal: Nature Aging (2022)

Abstract Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau P301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in Tau P301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
Author Correction: Impact of the COVID-19 pandemic on the kidney community: lessons learned and future directions
Authors: Duvuru Geetha, Andreas Kronbichler, Megan Rutter, Divya Bajpai, Steven Menez, Annemarie Weissenbacher, Shuchi Anand, Eugene Lin, Nicholas Carlson, Stephen Sozio, Kevin Fowler, Ray Bignall, Kathryn Ducharlet, Elliot K. Tannor, Eranga Wijewickrama, Muhammad I. A. Hafidz, Vladimir Tesar, Robert Hoover, Deidra Crews, Charles Varnell, Lara Danziger-Isakov, Vivekanand Jha, Sumit Mohan, Chirag Parikh, Valerie Luyckx
Journal: Nature Reviews Nephrology (2022)
Inhibition of GABAA receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity
Authors: Cuiyu Zhang, Yuping Zhou, Junjie Zheng, Nannan Ning, Haining Liu, Wenyang Jiang, Xin Yu, Kun Mu, Yan Li, Wei Guo, Huili Hu, Jingxin Li, Dawei Chen
Journal: The Journal of Experimental Medicine (2022)

Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5+ intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABAAR) are present in the gastrointestinal tract. However, the functioning of the GABAergic system in ISCs is poorly defined. We found that GABAAR α1 (GABRA1) levels increased in the murine intestine after chemoradiotherapy. GABRA1 depletion in LGR5+ ISCs protected the intestine from chemoradiotherapy-induced P53-dependent apoptosis and prolonged animal survival. The administration of bicuculline, a GABAAR antagonist, prevented chemoradiotherapy-induced ISC loss and intestinal damage without reducing the chemoradiosensitivity of tumors. Mechanistically, it was associated with the reduction of reactive oxygen species–induced DNA damage via the L-type voltage–dependent Ca2+ channels. Notably, flumazenil, a GABAAR antagonist approved by the U.S. Food and Drug Administration, rescued human colonic organoids from chemoradiotherapy-induced toxicity. Therefore, flumazenil may be a promising drug for reducing the gastrointestinal side effects of chemoradiotherapy.
Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group
Authors: Lindsey M Hoffman, Camilo Jaimes, Kshitij Mankad, David M Mirsky, Benita Tamrazi, Christopher L Tinkle, Cassie Kline, Aparna Ramasubramanian, Fatema Malbari, Ross Mangum, Holly Lindsay, Vincent Horne, David J Daniels, Sameer Keole, David R Grosshans, Tina Young Poussaint, Roger Packer, Sergio Cavalheiro, Brigitte Bison, Todd C Hankinson, Hermann L Müller, Ute Bartels, Katherine E Warren, Murali Chintagumpala
Journal: Neuro-Oncology (2022)

Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized.The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively.Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment.Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.
T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer
Authors: Huanhe Ni, Huanling Zhang, Lin Li, He Huang, Hui Guo, Lin Zhang, Chunwei Li, Jing-Xiao Xu, Cai-Ping Nie, Kui Li, Xiaoshi Zhang, Xiaojun Xia, Jiang Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments. Methods Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STING flox/flox , TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture. Results Increased STING, CCL22 level, FOXP3 + cells but decreased CD8 + cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STING flox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3 + cells but higher CD8 + cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4 + CD25 high FOXP3 + iTreg differentiation from both human and murine CD4 + -naïve T cells from WT and IFNAR −/− mice but not TKO or IRF3 −/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4 + -naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion. Conclusions These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.
Radio- or Chemotherapy Dose Escalation for Organ Preservation in Rectal Cancer?
Authors: Joanna Socha, Agnieszka Żółciak-Siwińska, Krzysztof Bujko
Journal: Journal of Clinical Oncology (2022)

Garcia-Aguilar et al 1 reported the outcomes of the randomized phase II OPRA study on 324 patients with stage II or III rectal cancer treated with total neoadjuvant therapy (TNT, ie, chemoradiation [54 Gy] combined with either induction or consolidation chemotherapy delivered for 4 months).Better organ preservation rate was achieved in the consolidation chemotherapy group, in which the proportion of patients who preserved the rectum at 3 years was as high as 53%.These impressive results were achieved at the cost of grade 31 acute toxicity occurring during TNT in 34% of patients, including 2% of toxic deaths.